Once-Only Flexible Sigmoidoscopy Screening in Prevention of Colorectal Cancer:
a Multicentre Randomised Controlled Trial
Atkin WS, Edwards R, Kralj-Hnas I, Wooldrage K, Northover JMA, Parkin DM, Wardle J, Duffy SW,
Cuzick, J. Lancet 28 April 2010; 375: 1624-33.
Clinical Scenario: 60yo M with HTN presents to clinic for routine f/u. He is feeling well and has no family
history of colon cancer. He has declined FOBT, flex sig and colonoscopy for cancer screening in the past
but now wants know what screening test he should undergo to decrease his risk of colon cancer.
Current Guidelines for Colon Cancer Screening for average risk patient
USPSTF: Starting at age 50 and continuing to age 75
- FOBT yearly or
- Flex sig every 5 years or
- Colonoscopy every 10 years
FOBT has been previously shown to decrease colon cancer mortality rate, a few examples:
Lindholm E, Brevinge H, Haglind E. Br J Surg. 2008 Aug;95(8):1029-36.
Heresbach D, Manfredi S, et al. Eur J Gastroenterol Hepatol. 2006 Apr;18(4):427-33.
Jørgensen OD, Kronborg O, Fenger C. Gut. 2002 Jan;50(1):29-32.
Study Design: Multicenter, randomized cntrolled trial at 14 UK centers. Patients recruited 11/94- 3/99.
Hypothesis: Only one flexible sigmoidoscopy screening between 55 and 64 years of age can
substantially reduce colorectal cancer incidence and mortality.
Inclusion Criteria: All men and women aged between 55 – 64 years registered with GP offices were
eligible. Eligible patients were sent an information brochure and questionnaire including: “If you were
invited to have the bowel-cancer screening test, would you take up the offer?”
Exclusion Criteria: Inability to provide informed consent; history of colorectal cancer, adenomas, or IBD;
severe or terminal disease; life expectancy less than 5 years; or sigmoidoscopy or colonoscopy within the
previous 3 years. Individuals with a strong FH of colon cancer or symptoms suggestive of colon cancer
were managed outside the trial.
Randomization: Those who reported they would take up the offer of screening were randomized to the
intervention group who were offered a flex sig appointment or a control group who was not contacted in a
1:2 ratio. Randomization was stratified by trial center, GP, household type. Sequentially numbered
randomization was done in blocks of 12 with a constraint of no more than three consecutive allocations to
one group within or across blocks.
Figure 1: 375,744 assessed 368,142 eligible  194,726 excluded170,432 randomized.
394 total were excluded from final analysis due to 162 deaths, 218 dx colon ca, 2 emigrated, 11 enrolled
twice due to changing GP and one person who reported the wrong birthday.
Screening procedure: Flex sig with polypectomy for small polyps and referral for colonoscopy for polyps
>1cm, >3 adenomas, tubulovillous or villous histology, severe dysplasia or malignant disease or >20
hyperplastic polyps above the distal rectum. Those with no polyps or low-risk polyps were discharged.
Mortality Statistics: Review of National Health Service Central Register and UK cancer registries,
Hospital episodes statistics, NHS Bowel Cancer Screening Programme databases. Causes of death were
certified by the Office of National Statistics and verification of assignment of colorectal cancer as an
underlying cause of death was reviewed by a blinded independent expert coder.
Primary Outcomes: Colorectal cancer incidence and mortality
Secondary Outcomes: Incidence of distal and proximal cancer, all-cause mortality and non-colorectal
cancer mortality
Initial sample size was calculated for 90% power to detect 20% difference in the incidence of colorectal ca
at 10 years and mortality at 15 years. Patients attended screening at a rate of 70% ( higher than the 55%
expected rate), so follow-up was only continued thru 11 years to show a significant difference in mortality.
Baseline characteristics for the groups were not reported.
Intention-to treat and per-protocol analyses were both done. (Will only discuss ITT given selection bias)
Kaplan-Meier estimates are flawed due violation of the proportionality assumption. A hazard ration
assumes the incidence rate for the outcome is constant. Since the study found so many incident cancers
at the time of screening, this skews the incidence curve significantly to the left in the first 3 years followed
by more of a plateau, rather than decreasing the steady risk over time.
RESULTS: 51% women, mean age of 60y, median follow up thru Dec 08 was 11.2 years
- 53% (194,726) took up offer of screening of whom 170,038 were randomized
- 57,099 were randomized to the intervention group
- 71% of those (40,621) attended a screening
- 95% of those (38,525) were discharged
- 5% (2,131) were referred for colonoscopy – 2051 received colonoscopy
Only colorectal cancers were included in the analysis – carcinoid, in-situ leisons, squamous or small cell
carcinomas, GIST, basosquamous ca, leiomyoscarcoma and lymphoma dx were excluded.
- 2,617 colorectal cancers dx in 2524 participants
- Distal cancer 1192 control / 386 intervention – 126 at screening
- Proximal cancer 628 control / 311 intervention – 14 at screening
- Incidence of distal cancer reduced 35%, proximal cancer 2%
- Mortality from colorectal cancer reduced 31%, no significant effect on overall mortality
o Rate per 100,000 person yrs 52-44 control, 36-30 intervention, Hazard ratio 0.68 – 0.69
- Number needed to screen
o to prevent colon cancer dx = 191
o to prevent death from colon cancer = 402- 489
Incidence of distal cancer in the post-screening period was low (figure 2c, 3)
Limitations:
No baseline characteristics reported
No information regarding screening that took place outside the trial
Per-protocol analyses emphasized in discussion
Conclusions:
This is a very large sample over a long follow-up period with evaluation of important outcomes. A
very impressive undertaking. The population is assumed to be homogeneous so may not be as
reflective of our patient population. The biases trend towards not demonstrating a difference (including
those who did not show up for flex sig, not including non-colon cancer dx). I would like to have more
information about the cancer dx outside the study – were these dx made by screening flex
sig/fobt/colonoscopy at a later time after planting the seed for screening or due to symptoms? Overall, I
think this is a robust analysis showing a clinically significant difference. I will encourage patients to
undergo a flex sig if they are reluctant about colonoscopy. Less prep, fewer complications, more readily
available, cheaper and now proven to decrease rate of cancer dx AND death but anatomically limited.
Future Studies
-SCORE with similar protocol in Italy
-PLCO in US screening every 3-5 years during 55 -74y, abn referred to PCP for dx w/u
-NORCCAP in Norway similar protocol once-only flex sig w/results after 7 years at which time no
reduction in cancer incidence has been detected